We have found that the lateral domain structures of lipids in membranes are targets of acute alcohol action, and targets of the adaptive response to chronic ethanol and nitrous oxide exposure. We have developed a colligative thermodynamic framework which provides a quantitative description of alcohol and anesthetic action on domain structure in membranes. NMR and ESR partitioning protocols have been developed in this laboratory to address and quantitate alcohol action. The thermodynamic theory was validated in for the action of alcohol in model membranes. Partitioning studies in microsomal liposomes indicate that chronic exposure to ethanolor nitrous oxide induces adaptations that alter domain formation and alcohol partitioning, in addition to inducing membrane tolerance's as determined by ESR spin-label order. Phosphatidylinositol is implicated as a determinant in these processes. Our aims are to determine the biophysical parameters and compositional factors governing the action of alcohols and anesthetics on domain formation. MASS-NMR offers the opportunity to simultaneously correlate structural, dynamical, and compositional information, and thereby supplement our present studies which report on bulk membrane properties and, therefore, rely on inter alia, comparisons between different systems to deduce the role of chemical makeup. We have found that phosphatidylethanol is an extremely potent membrane perturbant that destabilizes membranes by promoting the growth of highly curved lipid structures. No other phospholipid examined is as potent as this metabolite of ethanol. Thus dilute levels of both PtdIns and PtEth alter membrane behavior. It is anticipated that the elucidation of acute and chronic action of ethanol on membranes will provide a key understanding of ethanol related disease and the process of dependence and tolerance.